G?i/o-coupled receptor signaling restricts pancreatic ?-cell expansion.

ABSTRACT: Gi-GPCRs, G protein-coupled receptors that signal via G? proteins of the i/o class (G?i/o), acutely regulate cellular behaviors widely in mammalian tissues, but their impact on the development and growth of these tissues is less clear. For example, Gi-GPCRs acutely regulate insulin release from pancreatic ? cells, and variants in genes encoding several Gi-GPCRs--including the ?-2a adrenergic receptor, ADRA2A--increase the risk of type 2 diabetes mellitus. However, type 2 diabetes also is associated with reduced total ?-cell mass, and the role of Gi-GPCRs in establishing ?-cell mass is unknown. Therefore, we asked whether Gi-GPCR signaling regulates ?-cell mass. Here we show that Gi-GPCRs limit the proliferation of the insulin-producing pancreatic ? cells and especially their expansion during the critical perinatal period. Increased Gi-GPCR activity in perinatal ? cells decreased ?-cell proliferation, reduced adult ?-cell mass, and impaired glucose homeostasis. In contrast, Gi-GPCR inhibition enhanced perinatal ?-cell proliferation, increased adult ?-cell mass, and improved glucose homeostasis. Transcriptome analysis detected the expression of multiple Gi-GPCRs in developing and adult ? cells, and gene-deletion experiments identified ADRA2A as a key Gi-GPCR regulator of ?-cell replication. These studies link Gi-GPCR signaling to ?-cell mass and diabetes risk and identify it as a potential target for therapies to protect and increase ?-cell mass in patients with diabetes.

SUBMITTER: Berger M 

PROVIDER: S-EPMC4352814 | biostudies-other | 2015 Mar

REPOSITORIES: biostudies-other